RESUMO
Diabetes mellitus (DM) is a chronic systemic disease characterized by a multifactorial nature, which may lead to several macro and microvascular complications. Diabetic retinopathy (DR) is one of the most severe microvascular complications of DM, which can result in permanent blindness. The mechanisms involved in the pathogenesis of DR are multiple and still poorly understood. Factors such as dysregulation of vascular regeneration, oxidative and hyperosmolar stress in addition to inflammatory processes have been associated with the pathogenesis of DR. Furthermore, compelling evidence shows that components of the immune system, including the complement system, play a relevant role in the development of the disease. Studies suggest that high concentrations of mannose-binding lectin (MBL), an essential component of the complement lectin pathway, may contribute to the development of DR in patients with DM. This review provides an update on the possible role of the complement system, specifically the lectin pathway, in the pathogenesis of DR and discusses the potential of MBL as a non-invasive biomarker for both, the presence and severity of DR, in addition to its potential as a therapeutic target for intervention strategies.
Assuntos
Biomarcadores , Retinopatia Diabética , Lectina de Ligação a Manose , Humanos , Retinopatia Diabética/imunologia , Retinopatia Diabética/etiologia , Retinopatia Diabética/metabolismo , Retinopatia Diabética/diagnóstico , Lectina de Ligação a Manose/metabolismo , Animais , Lectina de Ligação a Manose da Via do Complemento , Suscetibilidade a Doenças , Ativação do Complemento/imunologiaRESUMO
BACKGROUND: The process of tissue injury in coronary artery disease (CAD) has been associated with activation of the complement system, partly due to the action of mannose-binding lectin (MBL) and C3, which are expressed in atherosclerotic lesions. OBJECTIVE: The aim of this study was to evaluate the serum levels of MBL and C3 in patients with CAD and to compare them with healthy controls. Additionally, we aim to assess the correlation between MBL and C3 levels and cardiometabolic parameters. METHODS: MBL and C3 serum concentration were determined by ELISA and immunoturbidimetry, respectively, in up to 119 patients undergoing coronary angiography for CAD evaluation, comprising 48 individuals diagnosed with acute myocardial infarction (MI) and 71 without MI. A total of 93 paired healthy controls were included in the study. RESULTS: Individuals with CAD had MBL serum concentration higher than controls (p = .002), regardless of the presence of MI (p = .006). In addition, high concentration of MBL (>2000 ng/mL) was more frequent in patients with CAD (p = .007; OR = 2.6; 95% CI = 1.3-5.1). C3 levels were not significantly associated with any of the patient groups but were positively correlated with cardiometabolic parameters such as body mass index (BMI) and triglycerides levels. CONCLUSIONS: Higher concentrations of MBL were found to be associated with CAD, whereas C3 levels were found to be associated with cardiovascular risk factors.
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Complemento C3 , Doença da Artéria Coronariana , Lectina de Ligação a Manose , Humanos , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico , Lectina de Ligação a Manose/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Transversais , Complemento C3/metabolismo , Complemento C3/análise , Idoso , Angiografia Coronária , Infarto do Miocárdio/sangue , Infarto do Miocárdio/diagnóstico , Biomarcadores/sangue , Índice de Massa Corporal , Estudos de Casos e ControlesRESUMO
Neutrophil extracellular traps (NETs) are cell-extruded DNA strands coated with neutrophils' nuclear proteins and enzymes from cytotoxic granules, produced by NETosis, a cell death pathway. They perform an important defensive role in innate immunity, but their increased production and/or inefficient degradation expose new antigens, such as DNA or citrullinated histone peptides, triggering autoimmunity. This study aimed to access possible associations between serum NETs levels with epidemiological, clinical, and serological data from a well-characterized SLE Brazilian patients' cohort. NET levels were evaluated in one hundred seventy serum samples of patients with Systemic Lupus Erythematosus (SLE) using an Immunoassay. Univariate and multivariate binary logistic regression used clinical patients' data as independent variables. Parametric and non-parametric tests compared log10 base serum NET levels transformed between patients' groups. SLE patients were also dichotomized into "High serum NET levels" and "Low serum NET levels" groups. All analyses were performed in R language 4.1.2, and p < 0.05 were considered significant. Increased susceptibility for high serum NET levels was observed in SLE patients with Raynaud's phenomenon (OR = 2.30, 95 % CI = 1.06-5.21 and p = 0.039), independently of any other risk factor. Also, SLE patients with Raynaud's phenomenon presented higher mean NET serum levels (mean = -0.13 vs. -0.51, p = 0.01). In addition, higher mean NET serum levels were associated with glomerulonephritis (mean = -0.45 vs. -0.12, p = 0.03). Ultimately, the SLEDAI index scored higher in the high NETs serum levels group (median = 2.0 vs. 0.0, p = 6 × 10-3). The formation of NETs might be implicated in Raynaud's phenomenon, glomerulonephritis, and disease index score in SLE patients. Our results highlight the importance of serum NET levels as a possible therapeutical target to modulate the clinical course of SLE.
Assuntos
Armadilhas Extracelulares , Lúpus Eritematoso Sistêmico , Doença de Raynaud , Humanos , Armadilhas Extracelulares/metabolismo , Armadilhas Extracelulares/imunologia , Feminino , Masculino , Brasil/epidemiologia , Adulto , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/imunologia , Doença de Raynaud/etiologia , Doença de Raynaud/sangue , Doença de Raynaud/imunologia , Pessoa de Meia-Idade , Neutrófilos/imunologia , Índice de Gravidade de Doença , Glomerulonefrite/sangue , Glomerulonefrite/imunologia , Glomerulonefrite/diagnóstico , Adulto Jovem , Biomarcadores/sangueRESUMO
Celiac disease (CD), despite its high morbidity, is an often-underdiagnosed autoimmune enteropathy. Using a modified version of the Brazilian questionnaire of the 2013 National Health Survey, we interviewed 604 Mennonites of Frisian/Flemish origin that have been isolated for 25 generations. A subgroup of 576 participants were screened for IgA autoantibodies in serum, and 391 participants were screened for HLA-DQ2.5/DQ8 subtypes. CD seroprevalence was 1:29 (3.48%, 95% CI = 2.16-5.27%) and biopsy-confirmed CD was 1:75 (1.32%, 95% CI = 0.57-2.59%), which is superior to the highest reported global prevalence (1:100). Half (10/21) of the patients did not suspect the disease. HLA-DQ2.5/DQ8 increased CD susceptibility (OR = 12.13 [95% CI = 1.56-94.20], p = 0.003). The HLA-DQ2.5 carrier frequency was higher in Mennonites than in Brazilians (p = 7 × 10-6). HLA-DQ8 but not HLA-DQ2.5 carrier frequency differed among settlements (p = 0.007) and was higher than in Belgians, a Mennonite ancestral population (p = 1.8 × 10-6), and higher than in Euro-Brazilians (p = 6.5 × 10-6). The glutathione pathway, which prevents reactive oxygen species-causing bowel damage, was altered within the metabolic profiles of untreated CD patients. Those with lower serological positivity clustered with controls presenting close relatives with CD or rheumatoid arthritis. In conclusion, Mennonites have a high CD prevalence with a strong genetic component and altered glutathione metabolism that calls for urgent action to alleviate the burden of comorbidities due to late diagnosis.
Assuntos
Doença Celíaca , Humanos , Doença Celíaca/epidemiologia , Doença Celíaca/genética , Prevalência , Brasil/epidemiologia , Estudos Soroepidemiológicos , IntestinosRESUMO
Gabiroba, a native fruit in Brazil's Atlantic Forest region, has significant nutritional and therapeutic properties. However, due to its seasonality, consumption by the population is limited. Thus, the development of gabiroba byproducts would add significant value to the food and therapeutic industries. Therefore, it is essential to study and support the lack of toxicity of gabiroba fruit extracts. In the present study, physicochemical analyses of fresh fruits (GF) and dehydrated whole gabiroba flour (WGF) and preliminary toxicity analyses of WGF were performed. The toxicity results showed a microcrustacean LC50 of >1000 mg/mL when exposed to WGF extracts at various concentrations (10-1000 µg/mL; p = 0.062) using the Artemia salina method, with no evidence observed of proliferative activity or toxic metabolic compounds in the WGF extract. The phytotoxicity of WGF using Lactuca sativa L. allowed germination and root growth at various concentrations of WGF extract, with the lowest (100 µg/mL) and highest (1000 µg/mL) concentrations exhibiting 98.3% and 100% seed germination, respectively. In conclusion, these results indicate that the WGF preparation preserved the nutritional and antioxidant potential of gabiroba fruits and that WGF is safe for use as a raw material in the food industry and for therapeutic purposes.
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Arctium lappa L., also known as burdock, is an edible wild plant which has the ability to grow in distinct environments and is considered a weed in several parts of the world. This species has great value in the biological and medical fields with its major secondary components being phenolic compounds and terpenes, substances rich in desired biological activities as antioxidant, antimicrobial, antitumor and anti-inflammatory. In addition, burdock leaves extracts have shown a modulatory effect on the complement system, which plays an important role in the development of inflammatory diseases, with an inhibitory effect on all complement pathways. Thus, natural products with those relevant activities are promising agents for healthcare applications. Therefore, the species A.â lappa may represent an interesting asset for researching and developing new therapies for inflammatory afflictions.
Assuntos
Arctium , Arctium/química , Extratos Vegetais/química , Antioxidantes/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/metabolismo , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/metabolismoRESUMO
The species Euphorbia umbellata has been used to treat inflammatory diseases, cancer, and ulcers. Biological activities reported in the literature, including antiproliferative, cytotoxic and anti-inflammatory, are attributed to the chemical constituents present in its composition as terpenes and polyphenolic compounds. The most recurrently verified metabolites in the Euphorbiaceae family plant species are terpenes, of which euphol is a major constituent with broadly reported cytotoxic, antinociceptive and anti-inflammatory effects; it frequently appears in various extracts obtained from the plant. Euphol has a documented inhibitory effect on neutrophil chemotaxis and can modulate the complement system. Since complement system activation is intimately intertwined with autoimmune and inflammatory diseases, tumor growth promotion and metastasis, plant metabolites from Euphorbia umbellata might influence the outcomes of inflammatory processes. We believe that this is the first review presenting the current knowledge on Euphorbia umbellata secondary metabolites and their biological activities.
Assuntos
Antineoplásicos , Euphorbia , Euphorbiaceae , Neoplasias , Humanos , Euphorbia/química , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Lanosterol/farmacologia , Anti-InflamatóriosRESUMO
INTRODUCTION: Chagas disease (CD), caused by Trypanosoma cruzi, is a major public health issue worldwide affecting 6-7 million people, mainly in Latin America. The complement system plays a crucial role in host immune defense against T. cruzi infection and during the chronic phase of CD; however, the role of the MBL-associated serine protease 1 (MASP1) gene encoding MASP-1, MASP-3, and MAp44 complement proteins has not yet been reported in CD. This study investigated the possible association between MASP1 gene polymorphisms and MASP-3 protein serum levels in chronic CD and its clinical forms. METHODS: Five polymorphisms of MASP1 gene regulatory regions were genotyped in 214 patients with CD and 197 healthy controls (rs7609662 G>A, rs13064994 C>T, rs72549262 C>G, rs1109452 C>T and rs850314 G>A). MASP-3 serum levels were assessed in 70 patients and 66 healthy controls. Clinical data, serum levels of complement proteins (ficolin-2, ficolin-3 and MBL) and inflammatory markers (pentraxin-3 and hsCRP) were also included in the analyses. RESULTS: A significant association of the MASP1 GC_CCA haplotype with CD (padj= 0.002; OR 3.17 [1.19-8.39]) and chronic chagasic cardiomyopathy (CCC) (padj= 0.013; OR 4.57 [1.37-15.16] was observed. MASP-3 and pentraxin-3 levels were positively correlated in the patients (rho = 0.62; p = 0.0001). MASP-3 levels were not associated with MASP1 polymorphisms or CD and its clinical forms. Furthermore, no correlation was observed between MASP-3 levels and that of ficolin-2, ficolin-3, MBL and hsCRP. CONCLUSION: Our findings suggest a possible role for the MASP1 GC_CCA haplotype in susceptibility to chronic CD and CCC clinical forms.
Assuntos
Doença de Chagas , Serina Proteases Associadas a Proteína de Ligação a Manose , Proteína C-Reativa , Doença de Chagas/genética , Proteínas do Sistema Complemento , Humanos , Serina Proteases Associadas a Proteína de Ligação a Manose/genética , Serina Proteases Associadas a Proteína de Ligação a Manose/metabolismo , Polimorfismo GenéticoRESUMO
AIMS: To investigate whether FCN3 polymorphisms and circulating ficolin-3 levels were associated with clinical forms of chronic Chagas disease (CD) and to assess their potential use as biomarkers for the disease or its severity. METHODS AND RESULTS: FCN3 polymorphisms (g.1637delC (rs532781899) in exon 5; g.3524_3532insTATTTGGCC (rs28362807) in intron 5 and g.4473C > A) (rs4494157) in intron 7) were determined in 178 chronic CD patients (65 asymptomatic, 68 cardiac, 21 digestive and 24 cardiodigestive), and 285 healthy controls by sequence-specific PCR. Ficolin-3 serum levels, measured by ELISA in 80 patients and 80 controls, did not differ between groups. On the other hand, ficolin-3 levels were positively correlated with left ventricular ejection fraction (P = .002; r = .5), with lower levels associated with increased risk of cardiac insufficiency (P = .033; OR 7.21, 95%IC 1.17-44.4). Ficolin-3 levels were positively correlated with ficolin-2 (P = .021; r = .63), and negatively with MBL (P = .002; r = -.36) and pentraxin-3 (P = .04; r = -.32) levels. No significant results were observed for the investigated FCN3 polymorphisms and CD. The g.1637del/1637C heterozygotes presented lower ficolin-3 levels than g.1637C/1637C homozygotes in the control group (P = .023). CONCLUSION: Low ficolin-3 levels may play a role in the pathophysiology of cardiac insufficiency associated with CD.
Assuntos
Doença de Chagas , Cardiopatias , Lectinas , Doença de Chagas/genética , Humanos , Lectinas/genética , Volume Sistólico , Função Ventricular EsquerdaRESUMO
The complement receptor of the immunoglobulin superfamily (CRIg, encoded by the VSIG4 gene) is a macrophage receptor involved in the clearance of immune complexes and autologous cells. Our results suggest that the VSIG4 rs1044165T allele is a risk factor for severe functional status of rheumatoid arthritis in women, possibly by affecting VSIG4 gene expression.
Assuntos
Artrite Reumatoide/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Receptores de Complemento/genética , Adolescente , Adulto , Idoso , Alelos , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/patologia , Brasil/epidemiologia , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Adulto JovemRESUMO
The complement system is a key component of the innate immunity that plays a significant role in the development and clinical presentation of Rheumatoid arthritis (RA). Complement protein C3 is a central molecule in the activation of complement with a significant role in the inflammatory processes of RA. Nevertheless, the impact of C3 gene polymorphisms in the development of RA is still unknown. The current study aimed to investigate the possible influence of C3 gene polymorphisms in the susceptibility and clinical expression of RA. Three C3 polymorphisms (rs2250656:A > G, intron 2; rs2230199:C > G [p.Arg102Gly], exon 3 and rs1047286:C > T [p.Pro314Leu], exon 9) were assessed by sequence-specific PCR in a total of 156 RA patients and 270 healthy controls from Southern Brazil. In addition, C3 levels were measured in 60 patients and 60 controls by immunoturbidimetry and clinical features were collected from medical records. The frequency of rs2230199 G allele and GG genotype was significantly higher in RA patients than controls (padj = 0.012 OR = 1.57 [1.11-2.31]; padj = 0.008, OR = 1.60 [1.35-2.33]) as well as the rs1047286 T and TT (padj = 0.010, OR = 1.67 [1.12-2.40]; padj = 0.001, OR = 1.83 [1.27-2.65] and the C3 AGT haplotype (padj = 0.0007 OR = 1.92 [1.32-2.80]). Moreover, C3 serum levels were higher in patients than controls (median: 169 mg/dl vs.155 mg/dl; padj = 0.022), as well as in RF seronegative compared with seropositive patients (172 mg/dl vs. 165 mg/dl; padj = 0.007). Our results suggest that the rs2230199 G (p.102Gly) and rs1047286 T (p.314Leu) alleles play a role in the pathophysiology of RA, possibly impacting complement activation by the alternative pathway.
Assuntos
Artrite Reumatoide , Predisposição Genética para Doença , Alelos , Artrite Reumatoide/genética , Estudos de Casos e Controles , Complemento C3/genética , Frequência do Gene , Genótipo , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Chronic inflammatory diseases lead to glycation of protein, lipids and nuclear acids. One product generated in this context is pentosidine. AIM: To study pentosidine levels in Systemic Lupus Erythematosus (SLE) and its possible association with disease activity and cumulative damage. METHODS: Pentosidine serum levels were measured in the serum by ELISA commercial kits in 79 patients with SLE. Disease activity index and cumulative damage were studied by SELENA-SLEDAI (Safety of Estrogen in Lupus National Assessment Systemic Lupus Erythematosus Disease Activity Index) and cumulative damage by SLICC/ACR DI (Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index for Systemic Lupus Erythematosus) respectively and simultaneously with determination of pentosidine levels. Epidemiological and clinical and serological profile were collected from the charts. RESULTS: In the 79 studied patients, the SLEDAI ranged from 0 to 12 (median of 0) and the SLICC/ACR-DI from 0 to 4 (median of 0). Serum pentosidine levels did not correlate with SLEDAI neither with SLICC. Patients with discoid skin lesions and photosensitivity had lower levels than those without them, with p â= â0.04 in both. CONCLUSION: In SLE, serum pentosidine levels did not reflect activity and cumulative damage. Patients with skin manifestations had lower levels of this biomarker.
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Rheumatic fever (RF) and chronic rheumatic heart disease (RHD) are complications of oropharyngeal infection caused by Streptococcus pyogenes. Despite the importance of the complement system against infections and autoimmunity diseases, studies on the role of the lectin pathway in RF and RHD are scarce. Thus, our aim was to evaluate the association of ficolin-3 serum levels, FCN3 polymorphisms and haplotypes with the susceptibility to RF and RHD. We investigated 179 patients with a history of RF (126 RHD and 53 RF only) and 170 healthy blood donors as control group. Ficolin-3 serum concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Three FCN3 single nucleotide polymorphisms (SNPs rs532781899, rs28362807 and rs4494157) were genotyped through the sequence-specific PCR method. Lower ficolin-3 serum levels were observed in RF patients when compared to controls (12.81 µg/mL vs. 18.14 µg/mL respectively, p < 0.0001, OR 1.22 [1.12-1.34]), and in RHD in comparison to RF only (RFo) (12.72 µg/mL vs. 14.29 µg/mL respectively, p = 0.016, OR 1.38 [1.06-1.80]). Low ficolin-3 levels (<10.7 µg/mL) were more common in patients (39.5 %, 30/76) than controls (20.6 %, 13/63, p = 0.018, OR = 2.51 [1.14-5.31]), and in RHD (44.4 %, 28/63) than RFo (15.4 %, 2/13, p = 0.007, OR = 3.08 [1.43-6.79]). On the other hand, FCN3 polymorphism/haplotypes were not associated with ficolin-3 serum levels or the disease. Low ficolin-3 levels might be associated with RF, being a potential marker of disease progression.
Assuntos
Suscetibilidade a Doenças , Lectinas/genética , Febre Reumática/etiologia , Febre Reumática/metabolismo , Cardiopatia Reumática/etiologia , Adulto , Alelos , Biomarcadores , Feminino , Predisposição Genética para Doença , Variação Genética , Genótipo , Humanos , Lectinas/sangue , Lectinas/metabolismo , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prognóstico , Febre Reumática/diagnóstico , Cardiopatia Reumática/diagnóstico , Cardiopatia Reumática/metabolismoRESUMO
INTRODUCTION: Patients with Chagas disease (CD), caused by Trypanosoma cruzi, present a higher risk of developing other chronic diseases, which may contribute to CD severity. Since CD is underreported in the southern state of Paraná, Brazil, we aimed to characterize clinical and epidemiological aspects of individuals chronically infected with T. cruzi in Southern Brazil. METHODS: A community hospital-based study was performed, recording clinical/demographic characteristics of 237 patients with CD from Southern Brazil. To estimate the association between different forms of CD and sociodemographic and clinical variables, multiple logistic regression models were built using the Akaike information criterion. RESULTS: Mean age was 57.5 years and 59% were females. Most patients' (60%) place of origin/birth was within Paraná and they were admitted to the CD outpatient clinic after presenting with cardiac/digestive symptoms (64%). The predominant form of CD was cardiac (53%), followed by indeterminate (36%), and digestive (11%). The main electrocardiographic changes were in the right bundle branch block (39%) and left anterior fascicular block (32%). The average number of comorbidities per patient was 3.9±2.3; systemic arterial hypertension was most common (64%), followed by dyslipidemia (34%) and diabetes (19%); overlapping comorbidities were counted separately. Male sex was associated with symptomatic cardiac CD (OR=2.92; 95%CI: 1.05-8.12; p=0.040). CONCLUSIONS: This study provided greater understanding of the distribution and clinical profile of CD patients in Southern Brazil, indicating a high prevalence of comorbidities among these patients who are a vulnerable group due to advanced age and substantial risk of morbidity.
Assuntos
Doença de Chagas , Trypanosoma cruzi , Brasil/epidemiologia , Doença de Chagas/diagnóstico , Doença de Chagas/epidemiologia , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , PrevalênciaRESUMO
Leishmania (Viannia) braziliensis is the main agent of mucocutaneous Leishmaniasis, a neglected tropical disease that affects thousands of people in Brazil. It has been shown that complement plays a critical role at early stages of Leishmania infection and that is involved in the invasion of macrophages by the promastigotes. Ficolins and collectins are soluble pattern recognition and triggering molecules of the lectin complement pathway. We investigated here whether lectin pathway activators ficolin-1, ficolin-2, ficolin-3 and CL-11 bind to live L. braziliensis promastigotes in vitro. Promastigote forms in the stationary growth phase were incubated with normal human serum (NHS) or recombinant ficolins 1, 2 and 3, MBL and CL-11, and protein binding was evaluated by confocal microscopy and flow cytometry. Ficolins 1, 2 and 3, MBL and CL-11 were able to bind to the surface of live promastigotes after incubation with either NHS or recombinant proteins. A partial inhibition by N-acetyl-d-glucosamine characterizing the participation of acetylated groups in the deposition of ficolins and CL-11 to glycoconjugates on the surface of L. braziliensis was observed. These evidences highlight a role for the lectin pathway in the innate response to L. braziliensis.
Assuntos
Colectinas/fisiologia , Lectinas/fisiologia , Leishmania braziliensis/imunologia , Proteínas do Sistema Complemento/fisiologia , Humanos , Imunidade Inata , FicolinasRESUMO
Rheumatoid arthritis (RA) is an autoimmune disease, which compromises the synovial membrane resulting in chronic inflammation. Ficolins are key proteins of the lectin pathway of complement able to recognize pathogen-associated molecular patterns, apoptotic cells, and cellular debris mediating the clearance by phagocytes. High ficolin-1 and ficolin-3 levels have been observed in RA patients, however, the influence of polymorphisms in the FCN1 gene in RA is not completely established, while no study evaluated FCN3 gene polymorphisms in RA to date. We investigated the influence of FCN1 and FCN3 gene polymorphisms in the susceptibility and clinical presentation of RA. A total of 148 patients with RA and up to 160 controls from Southern Brazil were genotyped by sequence-specific PCR (PCR-SSP) for five FCN1 promoter polymorphisms (rs2989727, rs10120023, rs17039495, rs10117466, and rs10858293) and three FCN3 gene variants (rs532781899, rs28362807, and rs4494157). The FCN1 g.-542GG (rs10120023) genotype and g.-542G allele, were associated with increased susceptibility to RA (p = .025, OR = 1.69 [1.07-2.69]; p = .041, OR = 1.47 [1.02-2.12], respectively) and related to decreased FCN1 gene expression in whole blood (p < .00001), according to gene expression databases. In addition, the FCN1 AAGAG haplotype was more prevalent in rheumatoid factor seronegative in comparison to seropositive patients (p = .006, OR = 0.042 [0.002-0.80]). There was no association of FCN3 polymorphisms with the susceptibility or clinical characteristics of RA. Our results indicate that the FCN1 rs10120023 [g.-542G>A] polymorphism in the promoter region might contribute to RA susceptibility, probably by impacting FCN1 gene expression.
Assuntos
Artrite Reumatoide/etiologia , Predisposição Genética para Doença , Lectinas/genética , Polimorfismo de Nucleotídeo Único , Alelos , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/metabolismo , Brasil , Proteínas do Sistema Complemento/imunologia , Expressão Gênica , Estudos de Associação Genética , Genótipo , Haplótipos , Humanos , Regiões Promotoras Genéticas , FicolinasRESUMO
BACKGROUND: Deposition of complement factors on Mycobacterium leprae may enhance phagocytosis. Such deposition may occur through the lectin pathway of complement. Three proteins of the lectin pathway are produced from the gene MASP1: Mannan-binding lectin-associated serine protease 1 (MASP-1) and MASP-3 and mannan-binding lectin-associated protein of 44 kDa (MAp44). Despite their obvious importance, the roles played by these proteins have never been investigated in leprosy disease. METHODOLOGY: We haplotyped five MASP1 polymorphisms by multiplex sequence-specific PCR (intronic rs7609662*G>A and rs13064994*C>T, exon 12 3'-untranslated rs72549262*C>G, rs1109452*C>T and rs850314*G>A) and measured MASP-1, MASP-3 and MAp44 serum levels in 196 leprosy patients (60%, lepromatous) and 193 controls. PRINCIPAL FINDINGS: Lower MASP-3 and MAp44 levels were observed in patients, compared with controls (P = 0.0002 and P<0.0001, respectively) and in lepromatous, compared with non-lepromatous patients (P = 0.008 and P = 0.002, respectively). Higher MASP-3 levels were present in controls carrying variants/haplotypes associated with leprosy resistance (rs13064994*T, rs1109452_rs850314*CG within GT_CCG and rs850314*A: OR = 0.5-0.6, Pcorr = 0.01-0.04). Controls with rs1109452*T, included in susceptibility haplotypes (GT_GTG/GT_CTG: OR = 2.0, Pcorr = 0.03), had higher MASP-1 and lower MASP-3 levels (P≤0.009). Those with GC_CCG, presented increasing susceptibility (OR = 1.7, Pcorr = 0.006) and higher MAp44 levels (P = 0.015). MASP-3 expression decreased in patients, compared with controls carrying rs1109452_rs850314*CA or CG (P≤0.02), which may rely on exon 12 CpG methylation and/or miR-2861/miR-3181 mRNA binding. CONCLUSION: Polymorphisms regulating MASP-3/MAp44 availability in serum modulate leprosy susceptibility, underlining the importance of lectin pathway regulation against pathogens that exploit phagocytosis to parasitize host macrophages.
Assuntos
Predisposição Genética para Doença , Hanseníase/genética , Hanseníase/patologia , Serina Proteases Associadas a Proteína de Ligação a Manose/análise , Serina Proteases Associadas a Proteína de Ligação a Manose/genética , Mycobacterium leprae/imunologia , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Estudos Transversais , Feminino , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Thousands of leprosy patients not only suffer from physical deformities, but also either have or have had hepatitis B virus (HBV) coinfection. Polymorphisms of the complement system modulate susceptibility to leprosy, but genetic susceptibility to past or present HBV infection is unknown. We used sequencing and multiplex sequence-specific PCR to genotype 72 polymorphisms of seven genes (MBL2, FCN1, FCN2, FCN3, MASP1, MASP2, C3) encoding components of the lectin pathway, and two genes encoding complement receptors (CR1, VSIG4) in 190 patients, of which 74 were positive for HBsAg and/or anti-HBc (HBV+, 93.2% with a resolved infection) and 116 lepromatous patients, and 408 HBV-blood donors. In addition, we tested for levels of proteins of the lectin pathway. We found no difference between serum concentrations of mannan-binding lectin (MBL), MBL-associated serine proteins (MASP-1, MASP-2, MASP-3, MAp44), ficolin-3 (FCN-3), soluble complement receptor 1 (sCR1) and MBL mediated C4 activation, measured by ELISA or TRIFMA in up to 167 HBV+ and HBV- patients. Haplotypes lowering protein levels or encoding dysfunctional proteins increased susceptibility to HBV infection: MBL2*LYQC (OR = 3.4, p = 0.02), MASP1*AC_CC (OR = 4.0, p = 0.015) and MASP2*1C2-l (OR = 5.4, p = 0.03). Conversely, FCN1*3C2 haplotype, associated with higher gene expression, was protective (OR = 0.56, P = 0.033). Other haplotypes associated with HBV susceptibility were: MASP2*2B1-i (OR = 19.25, P = 0.003), CR1*3A (OR = 2.65, P = 0.011) and VSIG4*TGGRCG (OR = 12.55, P = 0.014). Some polymorphisms in ficolin genes associated with lower protein levels increased susceptibility to leprosy/HBV infection: FCN*1 (OR = 1.66, P = 0.029), FCN2*GGGCAC (OR = 6.73, P = 0.008), and FCN3*del_del_C (OR = 12.54, P = 0.037), and to lepromatous disease/HBV infection: FCN2*TA (OR = 2.5, P = 0.009), whereas FCN2*MAG was associated with increased FCN-2 expression and resistance against coinfection (OR = 0.29, P = 0.026). These associations were independent of demographic factors and did not increase susceptibility to leprosy per se, except MASP2*1C2-l. Associations for FCN2, FCN3, MASP1, MASP2, and VSIG4 variants were also independent of each other. In conclusion, polymorphisms compromising activation of the lectin pathway of complement increase susceptibility to HBV infection, with ficolin polymorphisms playing a major role in modulating the susceptibility among leprosy patients.
Assuntos
Coinfecção/genética , Lectina de Ligação a Manose da Via do Complemento/genética , Hepatite B/genética , Hanseníase/genética , Receptores de Complemento/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Coinfecção/imunologia , Proteínas do Sistema Complemento/genética , Proteínas do Sistema Complemento/metabolismo , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Genótipo , Haplótipos , Hepatite B/imunologia , Vírus da Hepatite B , Humanos , Hanseníase/imunologia , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
Abstract INTRODUCTION: Patients with Chagas disease (CD), caused by Trypanosoma cruzi, present a higher risk of developing other chronic diseases, which may contribute to CD severity. Since CD is underreported in the southern state of Paraná, Brazil, we aimed to characterize clinical and epidemiological aspects of individuals chronically infected with T. cruzi in Southern Brazil. METHODS: A community hospital-based study was performed, recording clinical/demographic characteristics of 237 patients with CD from Southern Brazil. To estimate the association between different forms of CD and sociodemographic and clinical variables, multiple logistic regression models were built using the Akaike information criterion. RESULTS: Mean age was 57.5 years and 59% were females. Most patients' (60%) place of origin/birth was within Paraná and they were admitted to the CD outpatient clinic after presenting with cardiac/digestive symptoms (64%). The predominant form of CD was cardiac (53%), followed by indeterminate (36%), and digestive (11%). The main electrocardiographic changes were in the right bundle branch block (39%) and left anterior fascicular block (32%). The average number of comorbidities per patient was 3.9±2.3; systemic arterial hypertension was most common (64%), followed by dyslipidemia (34%) and diabetes (19%); overlapping comorbidities were counted separately. Male sex was associated with symptomatic cardiac CD (OR=2.92; 95%CI: 1.05-8.12; p=0.040). CONCLUSIONS: This study provided greater understanding of the distribution and clinical profile of CD patients in Southern Brazil, indicating a high prevalence of comorbidities among these patients who are a vulnerable group due to advanced age and substantial risk of morbidity.
Assuntos
Humanos , Masculino , Feminino , Trypanosoma cruzi , Doença de Chagas/diagnóstico , Doença de Chagas/epidemiologia , Brasil/epidemiologia , Doença Crônica , Prevalência , Pessoa de Meia-IdadeRESUMO
The complement system participates in host defense by eliminating microorganisms and triggering inflammation. However, insufficient control or exacerbated complement activation contributes to inflammatory diseases. Since promising antioxidant and anti-inflammatory activities have been identified in Arctium lappa L. extracts, this study aims to explore the effect of A. lappa extracts on the lectin pathway (LP) of complement activation. Four extracts were obtained by supercritical extraction using scCO2 with or without ethanol as co-solvent, at different temperatures and pressures (E1: 2.2â mg/mL, E2: 2.6â mg/mL and E3: 2.0â mg/mL, E4: 1.5â mg/mL). To evaluate the effect of A. lappa extracts on the LP activation, an ELISA assay using mannose binding lectin pathway of complement was carried out with C4 detection. All extracts showed a concentration-dependent inhibitory effect on the activation of complement by the LP. The following IC50 were observed for E1, E2, E3 and E4: 179.4â µg/mL, 74.69â µg/mL, 119.1â µg/mL and 72.19â µg/mL, respectively. Our results suggest that A. lappa extracts are potential candidates for the treatment of inflammatory disorders that are complement-related.